Human obesity is a recognized health problem with approximately eighty five million people considered clinically obese in the United States. Chronic imbalance between the amount of food intake and the energy expended by the body in its daily activities is the fundamental cause of obesity. The consequence of accumulation of surplus fat places overweight or obese individuals at increased risk of illness such as lipid disorders, type 2 diabetes, hypertension, migraine, coronary heart disease, stroke, osteoarthritis, respiratory problems such as chronic obstructivepulmonary disease (COPD) and asthma, sleep apnea and a wide variety of other metabolic diseases. Success in long-term treatment and/or prevention remains elusive. Obesity can be partially reversed or prevented by employing diet and behavior modification programs or by using pharmaceuticals. Among the most widely administered approved drugs are sibutramine and XENICAL®.
Sibutramine (MERIDIA®) is a CNS-active therapeutic for the treatment of obesity, which exerts its effects by acting as a norephinephime, serotonin and dopamine reuptake inhibitor. Sibutramine treatment is indicated for weight loss and is applied in combination with a reduced calorie diet. Sibutramine is contraindicated in patients with poorly controlled hypertension and patients with a history of cardiovascular heart disease.
Orlistat (XENICAL®) reduces the absorption of fatty acids by inhibition of triglyceride hydrolysis through its action as a gastric and pancreatic lipase inhibitor. Orlistat proved more effective than diet alone for weight loss, with improvements in total cholesterol, low density lipoprotein, the low density lipoprotein to high density lipoprotein ratio, and glycemic control. Side effects of Orlistat include mal-absorption of fat-soluble vitamins and steatorrhea.
A variety of biological targets are under clinical evaluation for the reduction of obesity in humans. Cannabinoid receptor 1 (CB1), a G-protein coupled receptor, contributes to the control of appetite by affecting brain reward systems. Acomplia (rimonabant), a selective CB1 endocannabinoid receptor antagonist, is under development for the treatment of obesity. A selective serotonine (5HT2C) agonist APD356 is under development for treatment of obesity.
Several selective β3 agonists are being evaluated in clinical trials. The β3-adrenergic receptor is found primarily in adipose tissue. It mediates a variety of metabolic functions such as lipolysis, thermogenesis and motility in the GI tract. The β3 agonists raise cAMP levels in brown and white adipose tissue, thus leading to activation of hormone-sensitive lipase and resulting in increased fatty acid oxidation and increased thermogensis by activation of UCP in brown adipose tissue.
Research addressing the potential role of leptin in the treatment of human obesity is ongoing. Leptin is produced in adipocytes and secreted in concentration proportional to the amount of adipose tissue. Obesity in humans is generally associated with high leptin levels. Daily subcutaneous injections of recombinant leptin results in weight loss as fat mass in some obese individuals.
Receptor subunits for the neurocytokine ciliary neurotrophic factor (CNTF) share sequence similarity with the receptor for leptin. Axokine is a modified CNTF. CNTF had been shown to affect appetite and body weight in rodents otherwise resistant to leptin treatment. When subcutaneously administered to humans, CNTF significantly affected appetite and body weight. A potential concern with the use of CNTF relates to a dose-dependent activation of latent herpes simplex infection.
Inducible nitric oxide synthase (iNOS) mediated NO overproduction causes insulin resistance in obese diabetic mice (Pilon et al., J. Biol. Chem., 2004, 279, 20767-74). Nitric oxide (NO) is a free radical that mediates several diverse biological events. Nitric oxide has a central role in the physiology and pathophysiology of the immune, central nervous and cardiovascular systems. The reactivity of NO toward molecular oxygen, thiols, transition metal centers and other biological targets enable it to act as a signal transduction molecule. Thus it controls diverse biological functions and is thought to be involved in the pathogenesis of autoimmune and inflammatory disease including septic, hemorrhagic shock, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, multiple sclerosis and disruption of the insulin signaling pathway (Kapur et al., Diabetes, 1997, 46, 1691).
Inducible NOS (iNOS) is induced by inflammatory cytokines in skeletal muscle and fat. The iNOS expression is increased in muscle and fat of genetic and dietary models of obesity. The iNOS induction in obese wild-type mice was associated with impairments in phosphatidylinositol 3-kinase and Akt activation by insulin in muscle. These defects were fully prevented in obese NOS-2+ mice. These findings provide some evidence that iNOS is involved in the development of muscle insulin resistance in diet-induced obesity (Perreault and Marette, Nature Med., 2001, 7, 1138). Interestingly it was observed that iNOS inhibitors do not block adjuvant arthritis in rats (Fletcher et al., J. Pharm. Exp. Ther., 1998, 284, 714).
Obesity-linked diabetes is also associated with a cytokine-mediated acute-phase or stress response, as reflected by increased systemic and tissue concentrations of the pro-inflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6 in obese human subjects and several animal models of obesity (Hotamisligil and Spiegelman, Diabetes, 1994, 43, 1271). TNF-α might be a mediator of insulin resistance in obesity since it interferes with insulin action and signaling in both skeletal muscle and adipose tissue. Other inflammatory cytokines such as IL-1, -6 and interferon (IFN)-γ have been also reported to inhibit insulin signaling in cultured adipose cells.
The agonists of the nuclear hormone receptor PPAR show strong bodyweight gain in obese diabetic model. These compounds cause fluid retention and adipogenesis (fat accumulation) in fibroblasts cells and result in fat laden adipocytes. It has been hypothesized that an antagonist of PPARγ, which blocks specifically the PPARγ induced fat accumulation, can be useful for the treatment of obesity (Mukherjee et al., Mol Endo, 2000, 14, 1425)). It was observed that some of the agonist also blocks the PPARγ induced adipogenesis in 3T3-L1 fibroblasts.